Diabetes involves dysfunction of the pancreatic islet cells. In the case of type 1 diabetes, also referred to as insulin dependent diabetes mellitus (IDDM), dysfunction is initiated in the event of an immunological challenge. In the case of type 2 diabetes, also referred to as non-insulin dependent diabetes mellitus (NIDDM), islet dysfunction occurs upon exposure to a homeostatic challenge. Diabetes is associated with total β-cell mass, as well as the properties of individual β-cells.
Type 1 Diabetes and Insulitis. Type 1 diabetes is a chronic autoimmune disease in which insulin-producing cells (β-cells) within the pancreatic islets of Langerhans are selectively targeted and destroyed by an infiltrate of immunological cells. This infiltrate causes an inflammatory affect on the islets, known as insulitis.
The development of type 1 diabetes is associated with an initial genetic susceptibility, although this susceptibility is insufficient for development of the disease. In susceptible individuals, it has been hypothesized that a triggering event leads to an active autoimmunity attack against β-cells, resulting in insulitis, islet β-cell dysfunction, diminished insulin secretion, and ultimately, β-cell destruction. β-cells comprise the majority of pancreatic islet cells. Overt type 1 diabetes onset characterised by hyperglycemia may not be diagnosed until years after an initial triggering event, at which point most of the pancreatic β-cells are destroyed. When overt diabetes is first recognised, some residual insulin production remains, as demonstrated by the presence of the connecting peptide (C peptide) of proinsulin in the serum. However, the individual usually requires injections of exogenous insulin. Complete β-cell destruction is determined when C peptide can no longer be detected in the circulation after stimulation with glucose or arginine.
The initiating factor(s) and specific sequence of events leading to type 1 diabetes, including the relative importance of different cell types and cytokines, are still widely debated. It is generally accepted that insulitis leading to type 1 diabetes involves cellular migration and infiltration of T lymphocytes, macrophages, and dendritic cells within the pancreatic islets. Immune stimulation of the newly infiltrated cells, and cytokine-regulated effects of such infiltration result in inflammation and β-cell destruction (Mandrup-Poulsen, 1996). Interleukin 1β (IL 1β), alone or in combination with tumor necrosis factor α (TNFα) and interferon γ (IFN γ), exhibits cytotoxicity toward β-cells in vitro (Cetkovic et al., 1994). This cytotoxicity is partly mediated through induction of free radicals such as nitric oxide (NO), the production of which is catalysed by inducible nitric oxide synthase (iNOS). NO released in β-cells leads to nuclear DNA fragmentation and apoptosis, a result which can be partially prevented by iNOS blockers. However, the blockers may not be used in vivo because of the various roles of NO in other organ systems.
Conventional treatment protocols for type 1 diabetes comprise regular administration, of insulin. Preferably, the insulin is administerered by injection. Other protocols have been suggested which include such immunomodulatory and immunosuppressive agents as levamisol, theophyllin, thymic hormones, ciamexone, antithymocyte globulin, interferon, cyclosporin, nicotinamide, gamma globulin infusion, plasmapheresis or white cell transfusion. Although these protocols may delay onset of type 1 diabetes, some undesirable side effects are observed. Treatment protocols after onset of type 1 diabetes are particularly problematic, since by the time diabetes is diagnosed in humans, insulitis has already progressed dramatically, resulting in a β-cell loss of more than 80%. Islet cell transplantation is a viable treatment for type 1 diabetes although graft rejection is still a major problem. Survival of transplanted islets requires effective immunosuppression, to block the immune response that leads to graft rejection. However, it is thought that the majority of islet death occurs in the first week post-transplant with up to 70% of β-cells also undergoing apoptotic cell death triggered by nonimmunological factors, such as hypoxia.
Type 2 Diabetes. Type 2 diabetes often occurs in the face of normal, or even elevated levels of insulin. The condition appears to arise from β-cell dysfunction, usually combined with impaired ability of tissues to respond appropriately to insulin (i.e. insulin resistance), which challenges the homeostasis of blood glucose. Over time, many individuals with type 2 diabetes show decreased insulin production and require supplemental insulin to maintain blood glucose control, especially during times of stress or illness.
Conventional treatments for type 2 diabetes have not changed substantially in many years, and have significant limitations. While physical exercise and a reduction in caloric intake can improve the condition, compliance with such regimens is generally poor. Oral anti-diabetic drugs—the sulfonylureas, biguanides (metformin), thiazolidediones, α-glucosidase inhibitors (acarbose, miglitol), meglitinides (nateglinide, repaglinide) and exenatide can also be used to maintain blood glucose levels. Insulin therapy may also be used as an adjunct or alternative to oral medication therapy.